This invention relates to regimens of administering compounds which are antagonists of the progesterone receptor in combination with a progestin, an estrogen, or both.
Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR antagonists may used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. NY. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N. Y. Acad. Sci., 761, 224, 1995).
Described by Jones, et al, (U.S. Pat. No. 5,688,810) is the PR antagonist dihydroquinoline A. 
Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998). 
Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998). 
Combs, et al., disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). 
Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994). 
Hamann, et al, described the PR antagonist J (Ann. NY Acad. Sci., 761, 383, 1995) 
Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997). 
Kurihari, et al., described the PR ligand L (J. Antibiotics, 50, 360, 1997). 
Kuhla, et al, disclosed the oxindole M as having cardiotoric activity (WO 86/03749). 
Weber, teaches the oxidole N for cardiovascular indications (WO 91/06545). 
Fischer, et al, describe a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516). 
Singh, et al, described the PDE III inhibitor P (J. Med. Chem., 37, 248, 1994). 
Andreani, et al, described the cytotoxic agent Q (Acta. Pharn. Nord., 2, 407, 1990). 
Binder, et al, described structure R which is an intermediate for preparing COX II inhbitors (WO 97/13767). 
Walsh described the oxindole S as an intermediate (U.S. Pat. No. 4,440,785, U.S. Pat. No. 4,670,566). 
R1=F, Cl, Br, alkyl, NH2 
R2=alkyl, alkoxy, F, Cl, NH2, CF3 
Bohm, et al, claim the oxindole T as cardiovascular agents (WO 91/06545). 
Bohm, et al, include the generic structure U (WO 91/04974). 
JP 63112584 A contains the generic structure V: 
Boar, et al, described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1). 
Kende, et al, described methodology for preparing 3,3-substituted oxindoles, e.g. X, that was utilized in the present invention (Synth. Commun., 12, 1, 1982). 
U.S Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin. The disclosed regimens also provide for use of an estrogen for a period of from 2-4 days to prevent breakthrough bleeding.
This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents. This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestins and progestins, an estrogen, such as ethinyl estradiol.
These regimens and combinations may be administered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the invention include stimulation of food intake. The uses herein for the treatment and/or prevention of the conditions or diseases described above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleeding.
The use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestin in combination with an estrogen or progestin or both. These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins.
The progestins of these combinations may be administered alone or in combination with an estrogen for the first 14-24 days of the cycle, the progestins being administered at a dosage range equal in progestational activity to about 35 xcexcg to about 150 xcexcg levonorgestrel per day, preferably equal in activity to from about 35 xcexcg to about 100 xcexcg levonorgestrel per day. An antiprogestin may then be administered alone or in combination with an estrogen for a period of 1 to 11 days to begin on any cycle day between day 14 and 24. The anti-progestin in these combinations may be administered at a dose of from about 2 xcexcg to about 50 xcexcg per day and the estrogen may be administered at a dose of from about 10 xcexcg to about 35 xcexcg per day. In an oral administration, a package or kit containing 28 tablets will include a placebo tablet on those days when the antiprogestin or progestin or estrogen is not administered.
In a preferred embodiment of this invention, the progestins of this invention may be administered alone or in combination with estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or in combination with an estrogen, for from 1 to 7 days.
The estrogen to be used in the combinations and formulations of this invention is preferably ethinyl estradiol.
Progestational agents useful with this invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestimate. Among the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and trimegestone.
Examples of orally administered regimens of this invention over a 28 day cycle include administration of a progestational agent solely for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 100 xcexcg of levonorgestrel. An antiprogestin compound of this invention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28. It is most preferred that the daily dosages of each relevant active ingredient be incorporated into a combined, single daily dosage unit, totaling 28 daily units per 28-day cycle.
In another regimen, a progestational agent may be coadministered for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, with an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 xcexcg. This may be followed as described above with an antiprogestin administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28.
Still another regimen within the scope of this invention will include coadministration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, being administered at a daily dose equal in progestational activity to from about 35 to about 100 xcexcg levonorgestrel, and an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 xcexcg. This will be followed on days 22 to 24 by coadministration of an antiprogestin (2 to 50 mg/day) and an estrogen, such as ethinyl estradiol, at a daily dose of from about 10 to about 35 xcexcg. From day 25 to day 28, this regimen may be followed by no administration or administration of a placebo.
This invention also kits or packages of pharmaceutical formulations designed for use in the regimens described herein. These kits are preferably designed for daily oral administration over a 28-day cycle, preferably for one oral administration per day, and organized so as to indicate a single oral formulation or combination of oral formulations to be taken on each day of the 28-day cycle. Preferably each kit will include oral tablets to be taken on each the days specified, preferably one oral tablet will contain each of the combined daily dosages indicated.
According to the regimens described above, one 28-day kit may comprise:
a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 xcexcg levonorgestrel;
b) a second phase of from 1 to 11 daily dosage units of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle in which no antiprogestin, progestin or estrogen is administered.
A preferred embodiment of this kit may comprise:
a) an initial phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 xcexcg levonorgestrel;
b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
Another 28-day cycle packaging regimen or kit of this invention comprises:
a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg; and
b) a second phase of from 1 to 7 daily dosage units of an antiprogestin of this invention at a daily dose of from about 2 to 50 mg; and
c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A preferred embodiment of the kit described above may comprise:
a) a first phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg; and
b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin administered at a daily dose of from about 2 to 50 mg; and
c) optionally, a third phase of 4 daily dose units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
A further 28-day packaged regimen or kit of this invention comprises:
a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg;
b) a second phase of from 1 to 7 daily dose units, each daily dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 xcexcg; and
c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A preferred embodiment of the package or kit just described comprises:
a) a first phase of 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably from about 35 to about 100 xcexcg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg;
b) a second phase of 3 daily dose units for days 22 to 24, each dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 xcexcg; and
c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
In each of the regimens and kits just described, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is administered. It is also understood that the daily dose units described are to be adrninistered in the order described, with the first phase followed in order by the second and third phases. To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle. It is further preferred that each package or kit comprise a pharmaceutically acceptable package having indicators for each day of the 28-day cycle, such as a labeled blister package or dial dispenser packages known in the art.
In this disclosure, the terms anti-progestational agents, anti-progestins and progesterone receptor antagonists are understood to be synonymous. Similarly, progestins, progestational agents and progesterone receptor agonists are understood to refer to compounds of the same activity.
These dosage regimens may be adjusted to provide the optimal therapeutic response. For example, several divided doses of each component may be administered daily or the dose may be proportionally increased or reduced as indicated by the exigencies of the therapeutic situation. In the descriptions herein, reference to a daily dosage unit may also include divided units which are administered over the course of each day of the cycle contemplated.
Compounds of this invention which may be used as the anti-progestational agents in the kits, methods and regimens herein are those of the Formula 1: 
wherein:
R1 and R2 are chosen independently from H, alkyl, substituted alkyl; OH, O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; 1 -propynyl; or 3-propynyl;
or R1 and R2 are joined to form a ring comprising one of the following: xe2x80x94CH2(CH2)nCH2xe2x80x94; xe2x80x94CH2CH2CMe2CH2CH2xe2x80x94; xe2x80x94O(CH2)mCH2xe2x80x94; O(CH2)pO; xe2x80x94CH2CH2OCH2CH2xe2x80x94; or xe2x80x94CH2CH2N(H or alkyl)CH2CH2xe2x80x94;
or R1 and R2 comprise a double bond to CMe2, C(cycloalkyl), O, or C(cyloether);
n is an integer from 0 to 5;
m is an integer from 1 to 4;
p is an integer from 1 to 4;
R3 is selected from H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, alkynyl or substituted alkynyl, or CORA;
RA is selected from H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
R4 is selected from H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alky, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
R5 is selected from the groups a), b) or c):
a) R5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: 
xe2x80x83wherein:
X is selected from the group of halogen, OH, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkyl, substituted C1 to C3 thioalkyl, S(O)alkyl, S(O)2alkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatomns, CORB, OCORB, or NRCCORB;
RB is H, C1 to C3 alkyl, substituted C1 to C3 alky, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
Y and Z are independently selected from H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkyl; or
b) R5 is a five or six membered heterocyclic ring with 1, 2, or 3 heteroatomns selected from O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group of H, halogen, CN, NO2 and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R6 is H, or C1 to C3 alkyl; or
c) R5 is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, lower alkyl, CN, NO2, lower alkoxy, or CF3;
or a pharmaceutically acceptable salt thereof
A preferred set of compounds of this invention is depicted by structure 2, 2a: 
wherein:
R5 is a disubstituted benzene ring containing the substituents X and Y as shown below: 
X is taken from the group of halogen, CN, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position of the disubstituted benzene ring selected from the group of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof
Another preferred group of this invention comprises compounds of formulas 2 and 2a wherein R5 is a five membered nrng with the structure shown below: 
U is O, S, or NR6,
R6 is H, or C1 to C3 alkyl, C1 to C4 CO2alkyl,
Xxe2x80x2 is selected from the group of halogen, CN, NO2, C1 to C3 alkyl or C1 to C3 alkoxy; with a proviso that, when Xxe2x80x2 is CN, U is not NR6;
Yxe2x80x2 is selected from H, F, CN, NO2 or C1 to C4 alkyl;
or a pharmaceutically acceptable salt thereof
Another preferred group of formulas 2 and 2a are those in which R5 is a six membered ring with the structure shown 
wherein:
X1 is N or CX2,
X2 is halogen, CN or NO2;
or pharmaceutically acceptable salt thereof
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula 1 and 2 the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms; xe2x80x9calkenylxe2x80x9d is intended to include both straight- and branched-chain alkyl group with 1 or 2 carbon-carbon double bonds and containing 2 to 8 carbon atoms; xe2x80x9calkynylxe2x80x9d group is intended to cover both straight- and branched-chain alkyl group with at least 1 or 2 carbon-carbon triple bonds and containing 2 to 8 carbon atoms.
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refers to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic systerm The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl as just defined having 1 to 4 substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, but are not limited to, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe the heterocyclic just defined having 1 to 4 substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cthioalkylxe2x80x9d is used herein to refer to the SR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9calkoxyxe2x80x9d is used herein to refer to the OR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9caryloxyxe2x80x9d is used herein to refer to the OR group, where R is aryl or substituted aryl, as defined above. The term xe2x80x9calkylcarbonylxe2x80x9d is used herein to refer to the RCO group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9calkylcarboxyxe2x80x9d is used herein to refer to the COOR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amnines wherein the alkyl or substituted alkyl groups, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, which may be either the same or different and the point of attachment is on the nitrogen atomn The term xe2x80x9chalogenxe2x80x9d refers to Cl, Br, F, or I.
The anti-progestational compounds of this invention may be prepared according to the methods described below. 
According to scheme 1, commercially available oxindole 5 is treated with mixture a strong organo-metallic base (e.g. butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide) in an inert solvent (e.g. THF, diethyl ether) under nitrogen at reduce temperature (ca. xe2x88x9220xc2x0 C.) (Kende, et al, Synth. Commun., 12, 1, 1982). The resulting di-anion is then treated with excess electrophile such as an alkyl halide, preferably the iodide. If R1and R2 are to be joined such as the product 6 contains a spirocycle at position 3, then the electrophile should be biftinctional, i.e. a diiodide. Subsequent bromination of 6 proceeds smoothly with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium acetate, to afford the aryl bromide 7. The bromide 7 is reacted with a palladium salt (e.g. tetrakis(triphenylphoshine)palladium(0)), in a suitable solvent (e.g. THF, dimethoxyethane, ethanol, toluene) at room temperature under an inert atmosphere (argon, nitrogen). The mixture is then treated with an arylboronic acid or boronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions. The required product 8 is then isolated and purified by standard means.
If R1 and R2 are different, then the intermediate 6 is prepared by reacting the dianion of 5 with one equivalent of the electrophile R1xe2x80x94X (X=leaving group e.g. I). The resultant mono-alkylated compound may be then isolated and re-subjected to the reaction conditions using R2xe2x80x94X, or alternatively used in-situ for the second alkylation with R2xe2x80x94X. Alternatively if the desired product 8 is to contain R2=H, then the isolated mono-alkylated intermediate is taken though the subsequent steps. 
Other methodologies are also available for coupling the pendant aryl group, Ar, to the oxindole platform, for example reaction of compound 7 with an aryl stannane, aryl zinc, or aryl magnesium halide in the presence of a palladium or nickel catalyst (scheme 2). The required aryl-metallic species described above are formed through standard techniques.
Other ftinctionalities can easily be installed into the 3-position of the indoline platform according to scheme 3. Oxidation of the unsubstituted indoline 9, preferably under neutral or acidic conditions (e.g. selenium dioxide in dry dioxane at reflux) affords the isatin 10. Compound 10 may be further functionalized to provide a ketal 11 by treatment with an alcohol and acid catalyst under dehydrating conditions. Alternatively reaction of 10 with a second ketone under suitable conditions (piperidine in toluene at reflux; or TiCl4/Zn in THF at reflux) affords alkylidene derivatives 12. Reaction of the isatin 10 with a grignard reagent or organolithium affords tertiary alcohols 13 (R=H). These alcohols may then be further ftmctionalized by alkylation or acylation procedures. 
Treatment of the bromide 7 in an anhydrous solvent (e.g. THF, Et2O) with a strong base (sodium hydride preferred, sodium hexamethyldisilazide, potassium hydride) followed by reaction at reduced temperature (xe2x88x9250 to xe2x88x9220xc2x0 C.) with n-butyllithium and N,N,N,Nxe2x80x2-tetramethylethylenediamine followed after a suitable period of time by a trialkylborate (trimethyl or triisopropylborate) gives after acidic work-up the boronic acid 14 (scheme 4). Compound 14 may then be reacted under palladium catalyzed conditions (tetrakis(triphenylphosphine)palladium(0), base (NaHCO3, Na2CO3, K2CO3, triethylamine, CsF) solvent (toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane) with an aryl bromide, aryl iodide, aryltrifluoromethane sulfonate of aryl fluorosulfonate, to provide the desired compounds 8.
An alternative strategy would be to prepare an organo zinc or magnesium reagent from compound 7 and react it in-situ with an aryl bromide, aryl iodide, aryltrifluoromethane sulfonate of arylfluorosulfonate, under palladium catalyzed conditions to afford compound 8. Such an organo zinc or magnesium species could be prepared by treatment of the bromide 7 in an anhydrous solvent (e.g. THF, Et2O) with a strong base (sodium hydride preferred, sodium hexamethyldisilazide, potassium hydride) followed by reaction at reduced temperature (xe2x88x9250 to xe2x88x9220xc2x0 C.) with n-butyllithium and N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine followed after a suitable period of time by reaction with anhydrous zinc chloride or magnesium bromide.
The anti-progestational compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional xe2x80x9cpro-drugxe2x80x9d forms, which, when administered in such form, convert to the active moiety in vivo.
When the compounds and combinations herein are employed for the utilities described above, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These combinations may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.